Welcome to our Grand Rounds Series. Each week, we plan to post a summary of the week’s Medicine Grand Rounds lecture. The summaries are reviewed and approved by the grand rounds speaker prior to posting.
Commentary by Ryan Farley MD, PGY-3
This week’s Medicine Grand Rounds guest lecturer was Dr. Barbara Kazmierczak , currently Associate Professor of Medicine and Microbial Pathogenesis at Yale University School of Medicine. Dr. Kazmierczak is the principal investigator for several NIH grants studying Pseudomonas aeruginosa virulence and host defense from their swarming, microscopic movement to the molecular determinants of epithelial attachment. She serves on several NIH study sections and as reviewer for the journals Molecular Microbiology, Infection & Immunity, and the Journal of Bacteriology.
Pseudomonas aeruginosa is an extremely versatile organism, able to inflict disease in a wide range of hosts, including mammals, insects and plants. In humans, the bacteria is responsible for complicating a variety of disease processes, especially in patients with underlying pulmonary disease such as cystic fibrosis, COPD/asthma and patients acutely hospitalized requiring ventilator assistance. Although the same organism is implicated in each type of patient, isolates of Pseudomonas employ different virulence factors that enable the organism to survive and inflict disease in a broad spectrum of clinical settings.
The pathogenesis of Pseudomonas can be divided into two main categories: acute infection and chronic persistence. Pseudomonas in acute infection relies upon a Type III Secretion System (T3SS). T3SS, expressed on the outer surface of the bacteria, punctures the host cell; in doing so, it injects bacterial toxins that ultimately lead to disease. These bacterial toxins include ExoY, ExoS, ExoT, and ExoU. The mechanism by which each toxin contributes to the pathogenesis varies; however, infection by a strain of Pseudomonas expressing ExoU carries an increased risk of developing acute Pseudomonal pneumonia. Chronic persistence on the other hand, is associated with the down-regulation of T3SS and the formation of a biofilm, an extracellular polysaccharide matrix, that is maintained by bacterial quorum sensing signals. Other bacterial virulence factors, such as flagella that enable movement, are also downregulated during chronic persistence, limiting immune detection and host clearance of Pseudomonas.
Understanding the pathogenesis of this organism in acute and chronic forms of infection has important clinical implications. Bacteria are increasingly becoming more resistant to our antibiotic armamentarium, especially Pseudomonas, necessitating newer agents designed to target vulnerable biologic pathways. A therapeutic agent that is able to block the T3SS might be useful in blunting bacterial invasion and tissue destruction. An agent that blocks the docking unit to the T3SS (anti-PcrV) is already in phase I clinical trials. Furthermore, current research is also focusing on quorum sensing inhibitors that would be useful as agents to disrupt biofilms in patients chronically colonized by this organism.